This invention relates to the diagnosis of Wegener's granulomatosis.
Wegener's granulomatosis is a disease of unknown cause and pathogenesis. Its major pathologic features are necrotizing granulomatous lesions, which most often affect the upper and lower airways, vasculitis, necrotizing glomerulonephritis and pulmonary capillaritis. Wegener's granulomatosis is a devastating illness, which without the early institution of immunosuppressive therapy can lead to rapid loss of renal function or massive pulmonary hemorrhage. Death occurs in over 80% of untreated patients within one year.
Patients with Wegener's granulomatosis have circulating autoantibodies directed against neutrophils and monocytes. The presence of these autoantibodies are useful in diagnosing the disease. The autoantibodies have usually been detected by indirect immunofluorescence assay, employing ethanol-fixed normal neutrophils as substrates. van der Woude et al. (1985) Lancet 1:425-429. Two staining patterns have been described: (1) cytoplasmic, and (2) nuclear or perinuclear. Andrassy et al. (1988) Nephron 49:257-258. The cytoplasmic pattern is detected in the majority of patients with active Wegener's granulomatosis, and is rarely found in other diseases. In contrast, the nuclear or perinuclear staining pattern is seen in only a very small percentage of patients diagnosed as having Wegener's granulomatosis, and is also observed in some patients with idiopathic necrotizing and crescentic glomerulonephritis, and in periarteritis with glomerulonephritis--so called microscopic polyarteritis. The antigen associated with the nuclear staining pattern has been shown to be myeloperoxidase (MPO), a primary granule component. The nuclear staining pattern results from artifactual redistribution due to ethanol fixation. Falk et al (1988) N. Engl. J. Med 318:1651-1657. The autoantigen associated with the cytoplasmic staining pattern is a soluble protein of 27-29 kilodalton (kD) localized to the primary or secondary granule fractions Gross et al. (1987) Lancet 1:1488-1489; Goldschmeding (1987) Kidney Int. 32:779.
The list of differential diagnosis in Wegener's granulomatosis is extensive and the early presentation can vary from a mild cough to renal failure. Without early treatment the disease is fatal in the vast majority of patients. Treatment, however, involves potentially toxic drugs, and clinicians may be reluctant to proceed without a definitive diagnosis. Accurate diagnosis of the disease is thus vital.